Films based on copolymers, their applications in transdermal systems and their processes of preparation

ABSTRACT

Films based on copolymers, their applications in transdermal systems and their processes of preparation. The said films consist of a hydrophobic polymer of ethylene/vinyl acetate (EVA) type containing at least one active principle and composed of 15 to 50% of hydrophilic inclusions formed from at least one hydrophilic monomer chosen from the group which comprises acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid or vinylsulphonic acids.

FIELD OF THE INVENTION

The present invention relates to films based on copolymers which arecapable of being used as active principle matrices in transdermalsystems, to transdermal systems containing the said films and to theprocess for the preparation of the said films and copolymers.

DISCUSSION OF THE BACKGROUND

Transdermal administration can, in certain cases, be a favourableadministration route for medicaments; in fact, such a route makes itpossible to optimize the systemic effect or topical effect, to increasethe therapeutic effectiveness, to reduce undesirable effects and toavoid, in the case of a systemic action, the effect of a first passagethrough the liver.

Transdermal systems are generally forms intended to make possible thepassage of active principles, incorporated in a reservoir, through theskin, either in order to have a systemic action or in order to obtain amore local action, by fixation in the underlying tissues of the skin.

Such systems can take essentially two forms:

a bag which acts as reservoir, limited on one of its surfaces by anadhesive semi-permeable membrane placed against the skin and whichcontrols the release and the passage of the active principle towards theskin; in this case, the membrane controls the release of the activeprinciples and therefore, in the case of a systemic action, their bloodconcentration.

a polymeric matrix which acts as reservoir and is associated with anadhesive, which controls the release towards the skin of the activeprinciple; this form contains two variants: (1) either the polymericmatrix consists of an adhesive, with responsibility for attaching thesystem to the skin, which acts as reservoir, (2) or the polymeric matrixand the adhesive are separate and only the polymeric matrix acts asreservoir and controls the release of the active principle, the onlyfunction of the adhesive being to hold the system onto the skin withouthindering the passage of the active principle.

The rate of release is thus controlled either by the membrane placedbetween the reservoir and the skin or by the reservoir itself (generallythen known as matrix).

Taking into account the above, many factors must be considered indeveloping a transdermal system.

It is, in particular, important to have available a reservoir whichmakes possible a steady release of the active principle, providing aconstant blood concentration or a sufficient concentration in theunderlying tissues, for a sufficiently long period of time (severaldays), so as to avoid excessively frequent applications of such systems.

Many systems have been proposed in the prior art and recommendparticularly the presence of a membrane which controls the release ofthe active principles and thus, in particular, their bloodconcentration.

In the case where the skin is not sufficiently permeable to the activeprinciple, permeability stimulators are combined with said activeprinciples.

Application EP 399 765, on behalf of Advanced Polymer Systems Inc.,describes particularly a transdermal system including an impermeablesupport and a matrix, made of appropriate adhesive material such as apolyisobutylene or an acrylic, and which includes a plurality ofpolymeric particles; these polymeric particles include at least onepenetration stimulator (or permeability stimulator), whereas the activeprinciple to be administered can be present either in the solid form orin the liquid form in the said matrix or in the said polymericparticles.

It is specified that the choice of the matrix and of the permeabilitystimulator are related to the active principle; in particular, when theactive principle is levonorgestrel, the matrix, which must be both areservoir for active principles and for polymeric particles, is EVA andthe stimulator is an ethyl acetate/ethanol mixture and is included inthe said polymeric particles, which can be prepared from unsaturatedmonoethylenic monomers (acrylic or methacrylic acid esters).

International Application WO 90/07940, on behalf of NovenPharmaceuticals Inc., describes a transdermal system which comprises anadhesive layer which includes the active principle and an impermeablesupport.

The adhesive layer is multipolymeric and advantageously comprises theactive principle, a multipolymer containing EVA and including an acrylicpolymer (adhesive), an elastomeric polymer (gum) and a tackifying agent.

The EVA copolymers (vinyl acetate: between 4 and 80 weight % andethylene: 15 to 90%) can be either copolymers or acrylicacid/ethylene/vinyl acetate terpolymers.

The EVA/acrylate ratio is preferably between 20:1 and 1:20 by weight. Acrosslinking agent can optionally be used. The compositionadvantageously comprises between 3 and 20% of EVA, between 25 and 70% ofacrylate and between 2 and 20% of gum.

International Application WO 91/16085, on behalf of Alza Corporation,describes adhesives based on polyisobutylene (PIB) for transdermalsystems.

It describes in particular a transdermal system comprising:

a reservoir containing nicotine and comprising from 60 to 95 weight % ofan EVA copolymer having a vinyl acetate content of approximately 40%,

an adhesive layer comprising nicotine dissolved in a polymer consistingessentially of a mixture of high molecular weight PIB and of lowmolecular weight PIB,

and an agent for controlling the release of the active principle,arranged between the reservoir and the adhesive.

European Patent 318,385, on behalf of Pierre Fabre Medicament, describesand claims a multilamellar device for the transdermal administration oftrinitrin composed successively of a support made of a flexible andocclusive material (EVA/PVDC/EVA-type co-extruded thermoplastic film),an active adhesive reservoir based on polymers of acrylic or siliconetype incorporating the active principle, a membrane for transfer of theactive principle of polyurethane type, a hypoallergenic adhesiveinterface self-fed by the reservoir with active principle, and aprotector made from a rigid or semi-rigid film coated with ananti-adhesive (ordinary paper, aluminized paper, polyesters or PVC),characterized in that it is constructed from a first module comprisingthe support, the active adhesive reservoir and a temporary protectivepaper and from a second module composed of the transfer membrane, theadhesive interface and the anti-adherent protector, the two modulesbeing bonded to each other, after removal of the protective paper fromthe first module, by pressing the active reservoir against the permeablemembrane for transfer of the active principle.

European Patent Application 328,806, on behalf of Paco PharmaceuticalServices, describes a transdermal system for estradiol which comprisesan impermeable; support and a matrix comprising from 60 to 95% of anadhesive polymer (vinyl acetate/acrylate multipolymer), from 5 to 20% ofa solvent (propylene glycol and derivatives), from 0.2 to 4% of a skinpenetration stimulator (polyoxyethylene ester,polyethyleneglycolsorbitan mono-9-octadecenoic acid ester) and from 0.5%of an active principle (oestrogen and derivatives).

These documents, taken as a whole, show the variety of the transdermaldevices containing particularly a polymeric matrix based on EVA;however, these devices of the prior art have a certain number ofdisadvantages:

the adhesive acts as reservoir, which only makes possible actions ofshort duration, excessively large active principle charges leading to aloss in adhesive power (limited capacity for charging with activeprinciple);

each of the systems is only suitable for a specific active principle;

the rate of release of the active principle is related to the nature ofthe adhesive.

These disadvantages particularly make it difficult, with thesetransdermal systems, to obtain controlled blood levels of activeprinciples, below the limiting flows due to the skin, lasting severaldays.

SUMMARY OF THE INVENTION

The present invention, for its part, has been devoted to the aim ofsupplying films capable of being used as active principle matrices intransdermal systems which correspond better to practical requirements,especially in that they can be suitable whatever the active principle,in that they make it possible to include, if necessary, significantconcentrations of active principles, in that they increase the stabilityon storage of the active principles and particularly of unstable activeprinciples and in that they are particularly well suited to producingcontrolled blood levels of active principles, below the limiting flowsdue to the skin, lasting several days (release of the active principleindependent of the adhesive).

The present invention has also been devoted to the aim of supplyingtransdermal systems containing the said films and the process for thepreparation of the said films.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents a summary diagram of the procedure according to anindirect method of the invention.

FIG. 2 shows desorption curves used in water at 37° C. on film disks ofExample 7.

FIG. 3 compares the results of charging a matrix with ethanol bydiffusion and by steeping (see Example 9).

FIG. 4 illustrates the degree of grafting obtained as a function ofgrafting time for Example 10.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The subject of the present invention is a film, capable of being used asactive principle matrix in a transdermal system, characterized in thatit consists of a hydrophobic polymer of ethylene/vinyl acetate (EVA)type containing at least one active principle and composed of 10 to 50%,preferably 15 to 50%, of hydrophilic inclusions formed from at least onehydrophilic monomer chosen from the group which comprises acrylamide,methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid,fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycolmethacrylate, methacrylamide, methacrylic acid, propylene glycolmethacrylate, hydroxyethyl methacrylate, dimethylaminoethylmethacrylate, N-vinylpyrrolidone, vinylacetic acid or vinylsulphonicacids.

The hydrophilic inclusions, within the meaning of the present invention,correspond to the abovementioned monomers which are polymerized, andoptionally crosslinked, and grafted onto the said hydrophobic polymer(EVA). The percentage of hydrophilic inclusions depends on the monomerchosen.

According to an advantageous embodiment of the said film, the EVAcomprises up to 40% of vinyl acetate, preferably 14 to 22%.

According to another advantageous embodiment of the said film, the saidhydrophilic inclusions are formed from acrylic acid.

According to an advantageous arrangement of this embodiment, thepercentage of acrylic acid is between 22 and 30%.

According to an advantageous mode of this arrangement, the saidcopolymer comprises EVA containing 14-33% of vinyl acetate, in which22-30% of acrylic acid are grafted.

The said film preferably comprises, as copolymer, EVA containing 14-22%of vinyl acetate, in which 26% of acrylic acid are grafted; such acopolymer is hereinafter known as EVA 18/AA 26.

One of the preferred compositions by weight of the said copolymer is:

    ______________________________________    Unit              %      parts    ______________________________________    Ethylene          65.1   82    Vinyl acetate     14.3   18    Acrylic acid      20.6   26    ______________________________________

The said film in accordance with the invention can also comprise, ascopolymer, EVA containing 30-36% of vinyl acetate, in which 26% ofacrylic acid are grafted; such a copolymer is hereinafter known as EVA33/AA 26.

Unexpectedly, such copolymers and particularly the copolymer EVA 18/AA26, as active principle matrix, provide films which simultaneouslydisplay:

mechanical properties (malleability and elasticity, particularly) whichare particularly well suited to their use in a transdermal system in theform of a film, which properties are not significantly detrimentallyaffected by the introduction of the active principle(s) or of othercharges and

a charge and desorption capacity of the active principle which is alsoparticularly well suited to a use in a transdermal system, which caneven be greater than 30 weight % with respect to the copolymer and whichmakes it possible to envisage treatment times of the order of sevendays.

In fact, the copolymers selected according to the present invention makepossible the incorporation (or charging), if necessary at highconcentrations, and the suitable desorption of many active principles orany other chemical substance, so as to obtain controlled blood levels ofthese products or active levels in the underlying tissues; suchcopolymers can additionally be charged with active principles indifferent ways (steeping, dispersion, diffusion, immersion in asaturated vapour atmosphere) and be convertible in the film form. Suchcopolymers also make possible an increased stabilization of the activeprinciples which they contain.

According to another advantageous embodiment of the said film, the saidhydrophilic inclusions are formed from a mixture of acrylic acid oracrylamide and N-vinylpyrrolidone.

In accordance with this embodiment, a film is obtained consisting of aterpolymer: EVA/AA/N-vinylpyrrolidone.

According to yet another advantageous embodiment of the said film, thesaid hydrophilic inclusions are formed from acrylamide.

The said film preferably comprises, as copolymer, EVA containing 14-22%of vinyl acetate, in which 26% of acrylamide (AAm) are grafted (EVA18/AAm 26).

Such a copolymer has a greater hydrophilic nature than that containingacrylic acid inclusions and makes possible the incorporation of veryhydrophilic active substances.

A percentage of less than 26% (of the order of 10-20%) makes it possibleto obtain a copolymer with a hydrophilic nature equivalent to that ofthe copolymer containing acrylic acid and whose mechanical propertiesare particularly well suited to their use in a transdermal system.

According to another advantageous embodiment of the said film, itsthickness is between 50 and 500 μm.

According to another advantageous embodiment of the said film, itcomprises up to 40% of active principle.

Mention may be made, as active principle and in a non-limiting way, ofNSAIs such as ketoprofen or ibuprofen, reproductive hormones such as17β-oestradiol, optionally in combination with a progestogen,anticholinesterases, medicaments for the cardiovascular system, such astrinitrin, products used in weaning from smoking addiction, such asnicotine, medicaments for pain (morphine), antiemetics or antimigrainemedicaments such as dihydroergotamine, as well as bromocriptine andsubstances for local use such as salicylic acid.

According to yet another embodiment of the said film, the said activeprinciple is combined with at least one permeability stimulator, such asalcohol or polyol.

Another subject of the present invention is a transdermal system of thetype comprising an occlusive support, an active principle reservoir, anadhesive interface and a protective film, characterized in that theactive principle reservoir consists of a film as defined above in whichthe hydrophilic inclusions are formed from at least one hydrophilicmonomer chosen from the group which comprises acrylamide, ethyleneglycol acrylate, methylolacrylamide, diacetone acrylamide, maleic acid,acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate,ethylene glycol methacrylate, methacrylamide, methacrylic acid,propylene glycol methacrylate, hydroxyethyl methacrylate,dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid orvinylsulphonic acids.

Advantageously, such a transdermal system is particularly well suited tocontrolling the release of all kinds of active principles and has a highabsorbing power of the said active principles.

Such properties are essentially linked to the characteristics of thesaid system, namely:

the reservoir consists of a polymeric matrix as defined aboveunexpectedly having the two-fold function of reservoir and ofcontrolling the release of the active principle(s);

the rate of release of the active principles is related solely to thenature of the polymeric matrix constituting the reservoir; this meansthat the adhesive, combined with the said polymeric matrix, does notmodify the rate of transfer of the active principle from the reservoirtowards the skin;

the greater adaptability of the polymeric matrix in accordance with theinvention to the active principles (one or several);

the ability of the polymeric matrix to be shaped in the form of a filmof appropriate thickness;

the ability of the polymeric matrix to stabilize some of the activeprinciples incorporated;

the high charging capacity of the polymeric matrix with activeprinciple.

According to a preferred embodiment of the said transdermal system, itcomprises:

an impermeable protective film comprising materials, used particularlyin the food or pharmaceutical industry, chosen from polyvinylidenedichlorides (PVDC), polyethylenes (PE), ethylene/polyvinyl alcohol,polypropylenes, polyesters or polychlorotrifluoroethylene,

an active principle matrix consisting of a film in accordance with theinvention,

an adhesive which is chemically inert with respect to the activeprinciple matrix and which does not interfere in its ability to desorbthe active principles, which adhesive is selected from acrylic polymers,polyurethane, silicones or EVA and

a protective sheet compatible with the adhesive selected (siliconepolyester, for example).

The impermeable nature of the protective film can be improved bycomplexing with a metal sheet, of aluminium for example, or by means ofany other plating process.

According to an advantageous arrangement of this embodiment, the film inaccordance with the invention, active principle matrix, is based on anEVA/AA copolymer, preferably an EVA 18/AA 26 copolymer.

According to another advantageous arrangement of this embodiment, thesaid film additionally comprises a stimulator of the permeability of thesaid active principle through the skin selected from non-toxicsubstances which are not a solvent of the polymeric matrix, such asalcohols and polyols (propylene gycol, PEG or ethanol, for example).

When the said transdermal system contains at least two activeprinciples, these are either distributed in the body of the polymericmatrix or in a different segment of the polymeric matrix.

Another subject of the present invention is a process for thepreparation of a film capable of being used as an active principlematrix in accordance with the invention.

The said process comprises:

(a) bringing EVA, in the powder, granule or film form, and hydrophilicmonomers into contact,

(b) the crosslinked polymerization of the said hydrophilic monomers andthe grafting, onto the EVA, of the hydrophilic polymer obtained(EVA/hydrophilic polymer copolymerization) by irradiation until anEVA/hydrophilic polymer copolymer is obtained in which the degree ofgrafting of the hydrophilic polymer is between 10 and 50%,

(c) the charging of the copolymeric matrix with active principle, ifnecessary, that is to say when the EVA is in the powder or granule form,

(d) the shaping of the copolymer obtained in the form of a film.

According to an advantageous embodiment of the said process, thecopolymerization stage (b) is carried out in liquid medium, in thepresence of an inhibitor of homopolymerization of the hydrophilicmonomers.

The said homopolymerization inhibitor is preferably a ferrous salt suchas Mohr salt when, for example, acrylic acid or acrylamide is used asthe hydrophilic monomer.

According to another advantageous embodiment of the said process, thecopolymerization stage (b) is carried out in liquid medium in thepresence of crosslinking agents chosen from the followingpolyunsaturated compounds: methylenebisacrylamide, divinylbenzene,triallyl cyanurate, ethylene, butylene and tetraethylene glycolacrylates or methacrylates, or triallyl orthophosphate.

This stage (b) is preferably carried out by irradiating the solutionwith an ionizing radiation for several hours, the total irradiation dosebeing between 0.5 and 50 kGy, in order to obtain the degree of graftingof the hydrophilic polymers between 10 and 50%.

The irradiation time depends on the dose rate and on the radiationsource used; it is preferably between 2 hours and 30 hours.

The sources of the ionizing radiation are particularly X-ray generators,particle accelerators and in particular electron accelerators, orsources containing ⁶⁰ Co and ¹³⁷ Cs radioactive isotopes, which areγ-ray emitters.

According to another advantageous embodiment of the said process, theactive principle charging stage (c) is carried out before the shapingstage (d).

According to another advantageous embodiment of the said process, theactive principle charging stage (c) is carried out after the shapingstage (d).

The said active principle charging stage (c) can preferably be carriedout:

either by steeping,

or by dispersion in the copolymer,

or by diffusion from a support impregnated with active principle,

or by immersion in a saturated vapour atmosphere.

It should, however, be noted that the method by steeping is problematicto implement industrially (safety, drying stage necessary, and the like)and leads to the use of a significant amount of active principles, muchgreater than the requirements of the application, and that, moreover,the method by dispersion in the copolymer is only applicable tothermostable active principles.

In contrast, the method of charging with active substance by diffusionfrom a support impregnated with active substance has surprisingly provedto be particularly effective and easy to apply industrially.

According to another embodiment of the said process, the shaping stage(d) is advantageously carried out by extrusion.

As a variant, the process for the preparation of the film capable ofbeing used as active principle matrix in accordance with the inventioncomprises:

(a) the irradiation of the EVA, in the powder, granule or film form, ata dose of between 10 and 80 kGy;

(b) the storage of the irradiated EVA for several weeks at roomtemperature or for several months at low temperature;

(c) the EVA/hydrophilic polymer copolymerization by bringing theirradiated EVA obtained in (b) into contact with hydrophilic monomersfor several hours, preferably for 5 to 20 h, in order to obtain anEVA/hydrophilic polymer copolymer in which the degree of grafting of thehydrophilic polymer is between 10 and 50%;

(d) the charging of the copolymer with active principle, if necessary,that is to say when the EVA is in the powder or granule form,

(e) the shaping of the copolymer obtained in the form of a film.

The measurement of the degree of grafting on test samples must be inaccordance with the invention (10-50%), after storage.

In the case where the EVA is in the film form, on conclusion of thegrafting and active principle charging stages, a simple calendering willmake it possible to bring the said film to the desired thickness.

Such processes of preparation make it possible:

to obtain a great variety of polymers, which is chosen as a function ofthe chemical substance or active principle to be charged; and

to remove the toxic risk related to the use of catalysts.

Another subject of the present invention is a process for thepreparation of an EVA/hydrophilic inclusions copolymer as defined above,characterized in that it comprises:

(a) the irradiation of the EVA, in the powder, granule or film form, ata dose of between 10 and 80 kGy;

(b) the storage of the irradiated EVA for several weeks at roomtemperature or for several months at low temperature;

(c) the EVA/hydrophilic polymer copolymerization by bringing theirradiated EVA obtained in (b) into contact with hydrophilic monomersfor several hours in order to obtain an EVA/hydrophilic polymercopolymer in which the degree of grafting of the hydrophilic polymer isbetween 10 and 50%.

The EVA/monomers contact time depends on the dose absorbed, on themonomer concentration and on temperature; it is preferably between 5 and20 hours.

According to an advantageous embodiment of the said process, the saidcopolymer obtained is charged with chemical substance according to oneof the charging methods defined above.

Such a process makes it possible to separate the stages of the processin time, which makes possible a better adaptation to industrialapplication and facilitates the storage of these copolymers.

Such copolymers are particularly suited to applications in the medical,farm-produce or agronomic field which require the controlled diffusionof one or several chemical substances from a solid support which can beshaped (implant, for example, and the like).

In addition to the preceding arrangements, the invention furthercomprises other arrangements which will emerge from the descriptionwhich will follow which refers to implementational examples of theprocess which is the subject of the present invention.

However, it must be well understood that these examples are given solelyby way of illustration of the subject of the invention, of which they donot constitute in any way a limitation.

EXAMPLE 1 Preparation of an EVA 18/AA 26 Copolymer Capable of Being Usedas a Film in a Transdermal System

A. Direct Method

I--Composition of the Reaction Mixture

An aqueous solution containing 18.56 kg of acrylic acid is prepared inthe presence of Mohr salt and then 60 kg of EVA 18, as a powder, areadded to the above solution.

The main characteristics of the solution obtained are:

aqueous phase total volume ≠174.1

aqueous phase/solid phase ratio (mass): 3.0

acrylic acid/EVA ratio (mass): 0.31

II--Irradiation (Oxygen-free Atmosphere):

Dose rate: 600 Gy·h⁻¹

Dose absorbed: 15 kGy

Time: 24 h (reaction end determined by assaying the residual acidity)

A degree of grafting with AA of 26% is obtained over approximately 24 h.

It should be noted that these parameters can vary according to theirradiation device used.

B. Indirect Method (2-stage Method)

1) Procedure:

Polymer support:

18%-22% EVA,

Irradiation:

dose absorbed≦40 kGy,

room temperature

Storage conditions:

room temperature (≈20° C.)

Grafting:

reaction mixture:

monomer: commercial grade acrylic acid

solvent: water

hompolymerization inhibitor: Mohr salt (c=8 g/l).

reactor:

glass nature

nominal volume 1000 ml

filling {polymer: 150 g {mother solution: 400<V_(ml) ≦750

operating conditions:

prior deaeration: pure nitrogen flow

temperature: 62.5°±0.5° C.

2) Results (9 experiments):

The following Tables I and II show the degree of grafting obtained byvarying the following parameters: irradiation time, storage time,monomer concentration and monomer/EVA ratio by weight.

                  TABLE I    ______________________________________                       Storage            AA in    Experiment Dose    time       AA/EVA  sol.    No.        (kGy)   (days)     Ratio   (g/l)    ______________________________________    1          20      14         0.4     150    2          40      14         0.4     120    3          20      4          0.4     120    4          40      4          0.4     150    5          20      14         0.6     150    6          40      14         0.6     120    7          20      4          0.6     120    8          40      4          0.6     150    9          30      9          0.5     135    ______________________________________

                                      TABLE II    __________________________________________________________________________    RESPONSES    Experiment (No.)    OBTAINED     1   2   3  4   5   6   7   8   9    __________________________________________________________________________    Time (h)          total  20  21 h 20                         48 6 h 45                                21 h 15                                    5 h 30                                        21 h 30                                            6 h 30                                                5 h 40          for τ = 15%                 10-11                     2 h 30                         5  3   4 h 15                                    3   9   4   2 h 15          for τ 28%                 20  12  50 5 h 45                                12  5 h 10                                        18  7   5    % Degree          acrylic a.                 27.9                     32.6                         26.9                            29.2                                46.1                                    29.3                                        33.1                                            28.4                                                30.4    of grafting,          consumption    estimated          increase                 28.9                     32.9                         22.3                            29.9                                47.4                                    30.7                                        33.3                                            27.1                                                28.4    from the          in mass    Yd/Acrylic   70  81  67 73  (77)                                    49  55  47  56    A. (%)    __________________________________________________________________________

It emerges from these experiments that the degree of grafting of 26% isreached in virtually all the experiments.

These results also show that this indirect method makes it possible toobtain:

a satisfactory agreement between the two methods of estimation of thedegrees of grafting, namely by assaying the residual acrylic acid andfrom the variation in polymer mass before and after grafting. Moreover,these results are corroborated by the subsequent counting of thecarboxyl sites attached to the material obtained,

a grafting time of between 5 and 20 h (No. 3 excepted),

a high yield/acrylic acid (Experiments 1, 2 and 4).

FIG. 1 represents a summary diagram of the procedure according to thisindirect method.

Both the direct method and the indirect method make it possible toobtain an EVA/AA copolymer in which there is a percentage of grafted AAof the order of 26%. This copolymer can exist in the powder, granule orfilm form, the powder form having a particle size of up to 500 μm.

EXAMPLE 2 Preparation of a Film in Accordance with the Invention

A. From a copolymer obtained in Example 1:

1) Either the film is produced directly by hot extrusion (in the case ofactive principles which do not withstand heat) and the film thusobtained is then charged with active principles and excipients(including the permeability stimulator, if necessary) which are notextrusion-resistant using one of the methods mentioned above(essentially steeping or diffusion);

2) or the copolymer obtained in Example 1 is mixed, until homogeneous,with the active principle(s), the permeability stimulators and the otherextrusion-resistant excipients (charging by dispersion or by immersionin a saturated atmosphere), the said mixture is then converted togranules (diameter: 2-3 mm; length: 4-5 mm) and the said granules areextruded while hot until a film is obtained in which other excipientscan be added by steeping or diffusion.

B. Tests carried out on the film obtained:

monitoring of the thickness of the film,

tear strength (NFQ 03-011 Standard),

tensile strength (NFT 54-102 Standard).

EXAMPLE 3 Preparation of a Film Charged with Ketoprofen and TransdermalSystem Obtained from this Film

1) Preparation of the EVA 18/AA 26 copolymer charged with ketoprofen:

The copolymer is obtained in accordance with Example 1.

2) Preparation of the EVA/AA, ketoprofen and propylene glycol mixture:

The film comprising ketoprofen is prepared according to Example 2,Method A.2).

The propylene glycol (PG) and EVA/AA are brought into contact for 24hours. The ketoprofen is then added and the mixture is stirred for 30minutes in a tilting mixer.

Granulation of the mixture:

The mixture is passed into a mixer equipped with its cutting system. Thegranules are stored in polyethylene bags.

Extrusion:

The EVA/AA-ketoprofen-propylene glycol granule is extruded using a diefor a flat film. A tension-cooling assembly is used at the die outlet.

After extrusion, the film obtained can have a controlled thicknessvarying from 200 to 300 μm, according to requirements.

3) Pharmaceutical formulating: transdermal system:

The various components of the said-transdermal system are combined byknown methods; a transdermal system is then obtained comprising, fromthe outside inwards (contact with the skin):

a flexible aluminized impermeable film (aluminium/polyethylene complex)(support) of suitable dimensions,

a layer of adhesive (XP 15362 B) diluted beforehand with ethyl acetate,

the copolymer-active principle film,

a protective film made of silicone polyester.

The system thus obtained is enclosed, for example in an envelope madefrom a rigid aluminized sheet (aluminium/polyethylene complex) weldedonto a sheet of double-faced (silver/white) rigid aluminized film.

A. Study of desorption and of the dose of active principle charge of thefilm obtained.

Desorption test:

Film used:

polymer: EVA 18/AA 26

charge of ketoprofen: 10% of PG: 25%,

thickness (mm): 0.30,

surface area (cm²): 7.06.

Operating conditions:

dissolution device: Dissolutest® (USP XX) Prolabo

desorption medium: 0.05M phosphate buffer,

pH: 6.5,

volume: 113 ml/cm²,

temperature: 32° C.,

test carried out at constant volume: 800 ml.

Analytical method:

measurement of the OD in UV spectro photometry at λ_(max) : 260 nm,

the concentration is calculated with reference to a calibration range.

Results:

Means and standard deviations of 6 experiments (Table III).

                  TABLE III    ______________________________________            Total       Yield of  Mean degree            amount      the       of    Period  desorbed    desorption                                  desorption    (hours) (mg)        (%)       (mg/24 h/cm.sup.2)    ______________________________________    0       0.0 ± 0.0                         0.0 ± 0.0    0.08    6.6 ± 0.4                        33.2 ± 2.0    0.17    8.0 ± 0.4                        40.1 ± 2.1    0.25    8.3 ± 0.5                        41.8 ± 2.4    0.33    8.4 ± 0.5                        42.3 ± 2.4    0.5     8.7 ± 0.5                        43.8 ± 2.6    0.67    9.0 ± 0.5                        45.3 ± 2.4    1       9.4 ± 0.5                        47.4 ± 2.7    1.5     9.9 ± 0.6                        49.9 ± 2.9    2       10.4 ± 0.6                        52.2 ± 2.8    4       11.8 ± 0.6                        59.3 ± 2.8    6       13.1 ± 0.7                        65.7 ± 3.6    8       14.1 ± 0.9                        71.0 ± 4.5    24      18.5 ± 1.1                        92.7 ± 5.5                                  2.61    48      19.9 ± 1.1                        99.8 ± 5.5    ______________________________________

B. Monitoring of the finished product: desorption of the transdermalsystem based on ketoprofen.

Monitoring of the active principle charge is carried out as above in A.

Results:

Means and standard deviations of 6 experiments (Table IV).

                  TABLE IV    ______________________________________            Total       Yield of   Mean degree            amount      the        of    Period  desorbed    desorption desorption    (hours) (mg)        (%)        (mg/24 h/cm.sup.2)    ______________________________________    0       0.0 ± 0.0                         0.0 ± 0.0    0.08    1.6 ± 0.5                         7.6 ± 2.6    0.17    2.1 ± 0.7                        10.1 ± 3.4    0.25    2.4 ± 0.9                        11.8 ± 4.2    0.33    2.7 ± 1.0                        13.2 ± 4.7    0.5     3.2 ± 1.1                        15.5 ± 5.5    0.67    3.6 ± 1.3                        17.3 ± 6.2    1       4.2 ± 1.5                        20.7 ± 7.2    1.5     5.0 ± 1.7                        24.3 ± 8.5    2       5.6 ± 1.9                        27.1 ± 9.3    4       7.1 ± 2.3                         34.8 ± 11.3    6       8.1 ± 2.4                         39.6 ± 11.7    8       8.9 ± 2.4                         43.4 ± 11.9    24      13.7 ± 2.6                         66.7 ± 12.5                                   1.03    48      16.4 ± 1.7                        80.2 ± 8.3    ______________________________________

EXAMPLE 4 Preparation of a Transdermal System According to the Invention(Active Principle: Trinitrin)

A preparation is carried out in a way analogous to that of Examples 1and 2, with EVA 33 as the starting hydrophobic polymer.

An }EVA 33/AA 26 copolymer is then obtained.

A. Study of desorption and of the dose of active principle charge of thefilm.

desorption test:

Film used:

polymer: EVA 33/AA 26,

AP charge as %: 17

thickness (mm): 0.30,

surface area (cm²): 7.06.

Operating conditions:

Dissolution device: Dissolutest® (USP XX) Prolabo,

desorption medium: deionized water,

pH: 4.5-5,

volume/unit of surface area of the film: 127 ml/cm²

temperature: 32° C.

test carried out at constant volume: 900 ml.

Analytical methods:

gas phase chromatography,

the concentration is calculated with reference to a calibration range.

Results:

                  TABLE V    ______________________________________            Total       Yield of   Mean degree            amount      the        of    Period  desorbed    desorption desorption    (hours) (mg)        (%)        (mg/24 h/cm.sup.2)    ______________________________________    0.08    2.0 ± 0.4                         5.6 ± 1.0    0.17    3.0 ± 0.4                         8.5 ± 0.9    0.25    3.7 ± 0.4                        10.7 ± 1.0    0.33    4.5 ± 0.4                        12.8 ± 1.1    0.5     5.6 ± 0.8                        16.0 ± 2.3    0.67    6.7 ± 0.6                        19.1 ± 1.8    1       8.6 ± 0.4                        24.5 ± 1.2    1.5     10.6 ± 0.9                        30.4 ± 2.1    2       12.8 ± 1.1                        36.5 ± 3.1    4       20.5 ± 2.0                        58.6 ± 5.4    6       26.6 ± 2.2                        76.2 ± 6.4    8       28.1 ± 1.4                        80.5 ± 3.7    24      37.5 ± 1.3                        107.3 ± 5.0                                   5.31    ______________________________________

B. Monitoring of the finished product: desorption of a transdermalsystem based on trinitrin prepared in accordance with Example 2.

Monitoring of the active principle charge is carried out as above in A.

Results:

Means and standard deviations of 5 experiments

                  TABLE VI    ______________________________________            Total       Yield of   Mean degree            amount      the        of    Period  desorbed    desorption desorption    (hours) (mg)        (%)        (mg/24 h/cm.sup.2)    ______________________________________    0       0.0 ± 0.0                         0.0 ± 0.0    0.08    1.0 ± 0.3                         3.6 ± 1.2    0.17    1.7 ± 0.5                         6.5 ± 1.9    0.25    2.2 ± 0.6                         8.2 ± 2.2    0.33    2.8 ± 0.9                        10.7 ± 3.3    0.5     4.7 ± 0.2                        18.0 ± 0.9    0.67    5.4 ± 0.5                        20.5 ± 2.0    1       6.7 ± 0.6                        25.5 ± 2.2    1.5     7.9 ± 0.5                        30.0 ± 1.8    2       9.1 ± 0.4                        34.4 ± 1.4    4       12.0 ± 2.0                        45.3 ± 7.6    6       14.7 ± 1.7                        55.8 ± 6.3    8       16.9 ± 1.1                        63.9 ± 4.1    24      21.3 ± 2.3                        80.7 ± 8.6                                   3.02    48      25.6 ± 4.4                         96.9 ± 16.7    ______________________________________

EXAMPLE 5 Comparison (Kinetics of the Absorption or of Desorption) ofEVA 18/AA 26 and of EVA 18/AA 33: Example of Nicotine

I--Absorption of nicotine by irradiated films:

A. Crosslinking of the films:

1. Nature of the films:

films obtained by extrusion of polymer powders:

a) EVA 33/AA 26

b) EVA 18/AA 26

c) EVA 33

thickness=0.3 mm and approximately 40 cm long are treated.

2. Protocol:

The films (40 cm) are placed in polyethylene sachets which are purgedand filled with nitrogen before being closed by welding.

B. Absorption on films:

1. Protocol:

46 ml of an approximately 2% solution of nicotine (w/v) in water for asample with a diameter of 24 mm and an exchange surface area equal to9.3 cm².

A film is prepared as specified in Example 2, Method A. 1) (steeping):absorption is carried out for, on the one hand, 3 hours and, on theother hand, 24 hours at 37° C. in a shaking water bath.

At the end of absorption, the samples are wiped dry. They cannot bedried in the normal way in an oven as the nicotine is very volatile.

2. Results:

The degrees of absorption are calculated by weight uptake of the sampleswith reference to a control which has been subjected to the sametreatment in water. They are calculated with respect to the finalweight.

The results are combined in Table VII.

                  TABLE VII    ______________________________________    Absorption of nicotine by different films                Wf          W       Absorption    Films       (g)         (mg)    (mg/g)    ______________________________________    Absorption for 3 hours - 2% nicotine    EVA 18/AA 26                0.1920      39      202    EVA 33/AA 26                0.2132      37.6    176    EVA 33      0.1704      1.4     8.2    Absorption for 24 hours - 2% nicotine    EVA 18/AA 26                0.1842      28.6    155.3    EVA 33/AA 26                0.2591      79.5    306.8    EVA 33      0.1709      2.4     14.0    ______________________________________     Wf: weight of the film; W: weight of nicotine

II--in vitro desoration of nicotine by the films obtained in I.

A. Desorption after an absorption of three hours. 1. Protocol:

films: EVA 18/AA 26 EVA 33/AA 26: t=0.3 mm

desorption volume: 46 ml of water per sample with a diameter of 24 mmand exchange surface area of 9.3 cm². Maintenance of the temperature at37° C. in a shaking water bath. Renewal of the medium every 2 hours.

2. Results:

They are combined in Tables VIII and IX.

                  TABLE VIII    ______________________________________    Desorption of the EVA 18/AA 26 films    (absorption of nicotine for 3 h)    Time     Desorption        Flow    (hour)   (mg)   (cumul)     (%)  (μg/h/cm.sup.2)    ______________________________________    2        5.05   5.05        13   272    4        3.25   8.30        21   173.5    6        1.40   9.70        25   76.5    8        1.65   11.35       29   90    10       1.30   12.65       32   69.5    12       1.15   13.75       35   61    14       1.10   14.85       38   57.5    ______________________________________

                  TABLE IX    ______________________________________    Desorption of the EVA 33/AA 26 films    (absorption of nicotine for 3 h)    Time     Desorption        Flow    (hour)   (mg)   (cumul)     (%)  (μg/h/cm.sup.2)    ______________________________________    2        3.45   3.45         9   185    4        2.10   5.55        15   112.5    6        1.70   7.25        19   90.5    8        1.70   8.95        24   91    10       1.05   10          27   56.5    12       1.9    11.9        32   102    14       1.3    13.2        35   69.5    ______________________________________

B. Desorption after absorption for 24 hours:

1. Protocol:

Films: EVA 18/AA 26 EVA 33/AA26 EVA 33 t=0.3 mm, s=9.3cm²

desorption volume: 46 ml of water per sample, maintenance of thetemperature at 37° C. in a shaking water bath.

Renewal of the medium every 2 hours.

2. Results:

They are combined in Tables X, XI and XII.

                  TABLE X    ______________________________________    Desorption of nicotine from EVA 33 films    (absorption for 24 h)    Time     Desorption        Flow    (hour)   (mg)   (cumul)     (%)  (μg/h/cm.sup.2)    ______________________________________    2        1.25   1.25        52   67    4        0.10   1.35        56   4.5    6        0.02   1.37        57   1    8        0.01   1.38        57.5 0.5    10       0.01   1.39        58   0.5    12       0.01   1.40        58   0.5    14       0.01   1.41        59   0.5    ______________________________________

                  TABLE XI    ______________________________________    Desorption of nicotine from EVA 18/AA 26 films    (absorption for 24 h)    Time     Desorption        Flow    (hour)   (mg)   (cumul)     (%)  (μg/h/cm.sup.2)    ______________________________________    2        7.1    7.1         25   383.5    4        3.4    10.5        37   182    6        2.5    13          46   135    8        1.2    14.2        50   68    10       1      15.2        53   54    12       0.8    16          56   43    14       0.7    16.7        59   37    ______________________________________

                  TABLE XII    ______________________________________    Desorption of the EVA 33/AA 26 films    (absorption for 24 h)    Time     Desorption        Flow    (hour)   (mg)   (cumul)     (%)  (μg/h/cm.sup.2)    ______________________________________    2        19.6   19.6        25   1055    4        6      25.6        32   325    6        4.1    29.7        37   250    8        2.5    32.2        40   135    10       1.9    34.1        43   103    12       1.8    35.9        45    95    14       1.7    37.6        47    90    ______________________________________

These data particularly show that EVA 18/AA 26:

makes it possible to rapidly reach the maximum absorption charge (seeTable VII);

has a rapid desorption rate.

EXAMPLE 6 Comparison of the Behaviour of EVA 18/AA 26 and of EVA 18/AA16: Example of Nicotine

                  TABLE XIII    ______________________________________    Synoptic table of the main results emerging from the    physicochemical analysis of the supports.                   Copolymer type    Comparision criterion                     EVA 18/AA 16                                 EVA 18/AA 26    ______________________________________    Percentage              C          68.7 ± 0.1                                     71.5 ± 0.3    composition              H          10.9 ± 0.1                                     11.4 ± 0. 1    (%)       O          18.2 ± 0.1                                     17.0 ± 0. 1              N          inf. at 1%  inf. at 1%    Exchange  (mEq · g.sup.-1)                          1.91 ± 0.11                                      2.87 ± 0.04    capacity    Estimated (%)        15.9 ± 0.9                                     26.0 ± 0.4    degree    of grafting    Mass loss (%)              150° C.                          1.3         0.6    by thermogravi-              250° C.                          3.3         1.9    metric analysis              400° C.                         25.3        22.1              500° C.                         91.7        90.8    Infrared  CH.sub.2   +           +    spectrometry              C═O ester                         +           +              C--O--C    +           +              C═O acid                         +           +              OH acid    +           +    Mass      72         +           +    spectrometry    (m/e)     86         +           +              99         +           +              13         +           +    Water-soluble              (%)         4.2         2.8    fraction    Toluene-soluble              (%)        62          51    fraction    ______________________________________

                  TABLE XIV    ______________________________________    Synoptic table of the main results emerging from the    behavioural study of the supports.                   Copolymer type    Comparison criterion                     EVA 18/AA 16                                 EVA 18/AA 26    ______________________________________    Charging  (min)      15          15    time of    the powders    Degree of (%)        35          25    charging    of the powders    Amount of (%)        379         148    water    after charging    Desorption    kinetics  (mg/45 min)                         78          74    of the powders    Degree of (mg · cm.sup.-2)                         7.78 ± 0.56                                     6.40 ± 0.30    charging    of the films    Increase in the      2.6         1.9    surface area    after    impregnation    Increase in the      1.4         1.3    surface area    after drying    Increase in          4.7         2.9    weight    after    impregnation    Increase in          2.0         1.8    weight    after drying    Amount of (mg · cm.sup.-2)                         24.1        17.1    water    after charging    Amount of (mg · cm.sup.-2)                         6.6         7.7    water    after drying    Desorption    kinetics    of the films    Half-life of the              (hour)     0.63        0.81    first phase    Half-life of the              (hour)     20.1        20.1    last phase    ______________________________________

These data also show the advantage of the EVA 18/AA 26 copolymer. Theamount of water absorbed during the charging is very markedly increasedin the case of the use of EVA 18/AA 26; this leads to a significantswelling of the film and detrimentally affects its mechanicalproperties.

EXAMPLE 7 Preparation of a Film Charged with Physostigmine andTransdermal System Obtained from this Film

1) Preparation of the EVA 18/AA 26 copolymer charged with physostigmineat 5 mg/cm² :

The copolymer is obtained in accordance with Example 1.

2) Preparation of the EVA/AA and physostigmine mixture:

The film comprising the physostigmine is prepared according to Example2, Method A. 1):

The incorporation of the physostigmine is carried out by impregnatingthe film in an ethanolic solution of physostigmine.

The charging conditions are the following:

composition of the H₂ O/EtoH solution: 80/20 (v/v);

concentration of the solution with physostigmine: 20 mg/ml;

steeping conditions; sheltered from the light and with stirring for 3hours.

Such a charging time makes it possible to obtain a degree of charge ofaround 5 mg/cm².

3) Pharmaceutical formulating: transdermal system:

The various components of the said transdermal system are combined byknown methods; a transdermal system is then obtained comprising, fromthe outside inwards (contact with the skin), the same constituents as inExample 3.

A. Study of the desorption and of the dose of active principle charge ofthe film obtained.

Desorption test:

Desorption curves were produced, in water at 37° C., on film diskscharged under the preceding conditions, 3 days and 38 days aftercharging. These curves are represented in FIG. 2 (abscissa: time(hours), ordinate: physostigmine charged (mg/cm²)).

A progressive desorption of the physostigmine released by the film isobserved.

50% of what had been fixed is desorbed over 3 hours (T50) and more than90% after 72 hours (T90). The non-releasable fraction is low (less than10%). The two curves are virtually identical, showing a stability of thedesorption conditions during the time spent (38 d).

B. Monitoring of the finished product: desorption of the transdermalsystem based on physostigmine.

Monitoring of the charge is carried out by HPLC assay, preceded by anextraction of the physostigmine from the film.

The stability of the degree of charge was verified over six weeks.Variation in the degree of charge with time was not revealed, thisdegree being constant at around 5 mg/cm².

C. Pharmacokinetic study of the release of the active principle from thesaid transdermal system.

Pharmacokinetic and pharmacological studies carried out in rabbitsduring the application of transdermal systems with diameters of 50, 20and 12 mm (19.63, 3.14 and 1.13 cm² surface area) showed that the plasmaphysostigmine concentrations are maintained at a plateau throughout theapplication time and its activity by modification of the cholinesteraseactivity.

The transdermal system delivers the physostigmine with an effective meanflow of 6.29±2.6 μg/h·cm².

The half-life of the physostigmine after removal of the patch isequivalent to the half-life after intravenous physostigmineadministration and assay of the physostigmine in the skin revealsnegligible physostigmine levels. There thus exists no reservoirphenomenon in the skin.

EXAMPLE 8 Preparation of a Film Charged with 17β-oestradiol andTransdermal System Obtained from this Film

1) Preparation of the EVA 18/AA 26 copolymer charged with 7%17β-oestradiol:

The copolymer is obtained in accordance with Example 1.

2) Preparation of the EVA/AA, 17β-oestradiol, propylene glycol andpolyethylene glycol 400 mixture:

The film comprising 17β-oestradiol is prepared according to Example 2,Method A.2):

The propylene glycol, the PEG 400 and the EVA/AA are brought intocontact for 24 hours, the 17β-oestradiol is then added and the mixtureis stirred for 30 min in a tilting mixer.

The preparation is then carried out as in Example 3.

When the film is produced, it is charged with ethanol either byimmersion in a saturated ethanol atmosphere (Example 2, Method A.2) orby diffusion from a support impregnated with ethanol (Example 2, MethodA.1) in order to increase the cutaneous passage of the estradiol.

3) Pharmaceutical formulating: transdermal system:

The various components of the said transdermal system are combined byknown methods; a transdermal system is then obtained comprising, fromthe outside inwards (contact with the skin):

a flexible aluminized impermeable film (aluminium/polyethylene complex)(support) of suitable dimensions: 40 cm²,

a layer of adhesive (XP 15362 B: acrylic copolymer) diluted beforehandwith ethyl acetate: 80 mg,

the copolymer-active principle film: 1200 mg, with 60 mg PEG 400 and 300mg PG,

a protective film made of fluorinated polyester: 40 cm².

The system thus obtained is enclosed, for example in an envelope madefrom a rigid aluminized sheet (aluminium/polyethylene complex) weldedonto a sheet of double-faced (silver/white) rigid aluminized film.

The various components of the transdermal system are subjected to thesame in vitro monitorings as previously (see Example 3).

Pharmacokinetic studies carried out on post-menopausal women during theapplication of 40 cm² transdermal systems showed that the 17β-oestradiolblood concentrations remain, for at least 4 days, the same asconcentrations accepted as being effective. The mean concentration is34±7 pg/ml between 0 and 96 hours, as the following results show:

Samples taken before exposure of the transdermal system in accordancewith the invention (t=-24 h) give the base level of 17β-oestradiol,which is of the order of 6±1 pg/ml.

Table XV below shows the mean values of the plasma concentrations fromthe transcutaneous passage of estradiol after application of atransdermal system in accordance with the invention for 96 h (n=4).

                  TABLE XV    ______________________________________    Time    Plasma concentrations    (hours) means         ±  standard deviation    ______________________________________    -24      6            ±   1     0      15            ±  12     5      55            ±  16     9      68            ±  28    24      47            ±  10    29      34            ±  12    33      35            ±  18    48      29            ±  17    72      28            ±  16    96      25            ±   8    120      8            ±   2    ______________________________________

EXAMPLE 9 Charging a Matrix with Ethanol by Diffusion from a Support(Nonwoven) Impregnated with Active Principle (17β-oestradiol).

                  TABLE XVI    ______________________________________               Mean alcohol content (n = 2)    Transfer time                 (mg)        (%)    ______________________________________    1.5          6.9         21    4            8.8         28    6            9.1         27    24           9.0         27    48           9.7         29    ______________________________________

This Table XVI shows the results of charging a film charged with17β-oestradiol in accordance with Example 8 with ethanol by diffusionfrom a nonwoven support impregnated with ethanol.

This illustrates that, from 1 h 30, degrees of charging with ethanol areobtained which are sufficient for transdermal application.

FIG. 3 compares this new method of charging (diffusion) with charging bysteeping, the disadvantages of which were recalled above, and shows theequivalence of these charging processes.

EXAMPLE 10 Preparation of an EVA/AAm Copolymer Capable of Being Used asFilm in a Transdermal System

1) Procedure:

The preparation of the solutions, the degassing, the grafting, thewashings and the drying are carried out as specified in Example 1, withacrylamide as the hydrophilic monomer.

In particular, irradiation of EVA 20 (Exxon) is carried out at a dose ofbetween 20 and 40 kGy and is followed by an ageing at room temperatureof between 4 and 10 days; the acrylamide (AAm)/EVA ratio by mass isbetween 0.4 and 0.6 and the concentration of acrylamide in aqueoussolution of the order of 150 g.l⁻¹.

More precisely, the procedure comprises:

a) irradiation of the sample with a dose of 40 kGy under a 17 MeVelectron beam, resulting from a linear accelerator and characterized bya dose rate of the order of 1.5×10⁶ Gy.h⁻¹, according to the operatingconditions adopted,

b) heating while sheltered from the air for 7 h at 60° C. in a 20%acrylamide solution in water containing 4 g.l⁻¹ of Mohr salt.

After washing and drying, a degree of grafting equal to 25% is found bygravimetry, the grafting kinetics being monitored by refractometry or UVspectrophotometry on samples withdrawn at intervals from the graftingsolution.

2) Results (4 tests):

Table XVII shows the degree of grafting obtained by varying thefollowing parameters: irradiation time, storage time (ageing), monomerconcentration and monomer/EVA ratio by weight.

                                      TABLE XVII    __________________________________________________________________________       Dose Ageing  Reaction                         Time Time τ estimated                                         τ    Test       absorbed            time                AAm/                    time τ = 15%                              τ = 28%                                   by UV by weight    No.       (kGy)            (days)                EVA (min)                         (min)                              (min)                                   (%)   (%)    __________________________________________________________________________    1  30   9   0.5 360  230  375  27.3  33.0    2  40   7   0.6 285  100  290  27.8  26.8    3  20   4   0.6 375  --   --         18.3    4  40   7   0.4 375  290  530  19.5  21.6    __________________________________________________________________________

It emerges from these tests that the degree of grafting of 26% isachieved in virtually all the experiments; it is observed that there isreasonable equivalence between the values of the degree of graftingestimated by UV spectrophotometry and by weight.

These results also show that:

the rate of grafting becomes faster as the dose absorbed becomes greater(Tests 2 and 3),

the amount of acrylamide with respect to EVA is high (Tests 2 and 4),

AAm Test No. 1 shows kinetic parameters similar to those of Test No. 9of grafting with acrylic acid, carried out under the same conditions,

the best results obtained with acrylamide (AAm Test No. 2) are alsocomparable to those obtained with acrylic acid (Test No. 4).

3) Characterization of the copolymers obtained:

As in the case of acrylic acid, the EVAs grafted with acrylamide werecharacterized by different techniques in order, on the one hand, toverify their structure (nature of the grafts, degree of grafting, andthe like) and especially to verify that they possessed the hoped-forhydrophilic properties.

a) Elemental analysis:

This technique, not suited to EVAs grafted with acrylic acid, is againof interest on account of the introduction of a heteroatom, in this casenitrogen. The content of this element, which is not present in thestarting EVA, is capable of varying sufficiently significantly to beable to be correlated, without too much error, with the degree ofgrafting with acrylamide.

Thus, if the respective fractions by weight of ethylene, vinyl acetateand acrylamide in the grafted polymer are known as x, y and z (on thebasis of x+y =100% and z=τ), there is obtained: ##EQU1##

Comparison of the different values of the degree of grafting (estimatedvalues, values by weight and values recalculated from the nitrogencontent) discloses great similarity. On the one hand, for the samesample, with one exception, the nitrogen content varies little from onesampling to another, which testifies to homogeneous grafting. On theother hand, the recalculated degrees of grafting agree very well withthe other values and thus confirm the validity of the kinetic monitoringby UV.

                  TABLE XVIII    ______________________________________    Test               Degree of grafting (%)    No.  % C    % H    % N   recalculated from % N                                           by weight    ______________________________________    1    70.14  11.66  5.02  34.0         70.25  11.90  4.40  28.6   30.6 ± 2.4                                             33.0         69.63  11.27  4.47  29.2    2    71.32  11.59  3.89  24.5         72.46  11.75  3.71  23.1   24.6 ± 1.3                                             26.8         70.76  11.20  4.12  26.3    3    74.18  11.64  2.95  17.5         73.59  11.64  3.01  18.0   17.7 ± 0.2                                             18.3         73.69  11.42  2.96  17.6    4    73.44  11.18  3.43  21.0         72.79  11.36  3.56  22.0   21.5 ± 0.5                                             21.6         72.26  11.22  (6.57)                             (49.8)    ______________________________________

b) Moisture uptake:

The hydrophilicity of the grafted polymers was evaluated from theirmoisture uptake Wm (expressed in %o by mass). This characteristic ofeach material is related to its structure by an additivity relationshipwhich, in the case of the grafting of acrylamide, is expressed accordingto the relationship (1): ##EQU2## where the Hi values represent theelementary contributions of the hydrophilic links. The latter are afunction of the relative humidity and are calculated by interpolation ofthe Van Krevelen values:

                  TABLE XIX    ______________________________________    Relative humidity RH (%)                     44     65       81   97    ______________________________________    Hi(CO.sub.2 CH.sub.3)                     0.04   0.07     0.11 0.19    Hi(CONH.sub.2)   0.45   0.69     1.16 1.85    ______________________________________

The following Table shows a synthesis of the experimental results (firstvalue) and of the values recalculated from the relationship (1) with thedegree of grafting by weight (first parenthesis) or the degree from thenitrogen content (second parenthesis):

                                      TABLE XX    __________________________________________________________________________    Degree of grafting                   Moisture uptake    (%)            at equilibrium, Wm (%)    Test No.         by weight               % N RH = 44%                         RH = 65%                               RH = 81%                                     RH = 97%    __________________________________________________________________________    1    33.0  30.6                   23(30)(28)                         42(46)(43)                               62(76)(72)                                     174(122)(116)    2    26.8  24.6                   16(26)(24)                         30(39)(37)                               51(66)(62)                                     121(105)(99)    4    21.5  21.5                   15(22)(22)                         26(33)(33)                               46(56)(56)                                     123(90)(90)    __________________________________________________________________________

As in Example 1 (EVA grafted with acrylic acid), the moisture uptakeincreases with the relative humidity (RE) and, for a given relativehumidity, with the degree of grafting.

If these experimental values are compared with those obtained above foracrylic acid, it is noticed that, for a comparable degree of grafting(of the order of 25 to 30%), the moisture uptake of the EVAs graftedwith acrylamide is approximately 10 to 20% greater than that of theiracid homologues.

FIG. 4 illustrates the degree of grafting obtained (estimated by UV in%) as a function of the grafting time (minutes).

Grafted copolymers are obtained which are more hydrophilic than thoseobtained with acrylic acid.

EXAMPLE 11 Preparation of an EVA/acrylic Acid Copolymer Capable of BeingUsed as Film in a Transdermal System

The EVA is directly used in the film form (film with a thickness of 70μm).

The procedure comprises:

a) irradiation of the sample (dose rate =5 kGy.h⁻¹, dose absorbed: 30kGy) Cobalt-60 source

b) heating for 8 hours at 60° C. in an oxygen-free medium in a 25%aqueous acrylic acid solution containing 20 g.l⁻¹ of Mohr salt.

In addition to that which emerges from the above, the invention is in noway restricted to those of its implementations, embodiments andapplication modes which have just been described more explicitly; on thecontrary, it embraces all the variants thereof which can come to themind of a technologist in the subject, without departing from thecontext or from the scope of the present invention.

We claim:
 1. A film, capable of being used as an active principle matrixin a transdermal system, comprising:a hydrophobic ethylene/vinyl acetatepolymer containing at least one active principle and composed of 10-50wt. % of hydrophilic inclusions consisting of a hydrophilic polymerformed from at least one hydrophilic monomer selected from the groupconsisting of acrylamide, methylolacrylamide, diacetone acrylamide,maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycolacrylate, ethylene glycol methacrylate, methacrylamide, methacrylicacid, propylene glycol methacrylate, hydroxyethyl methacrylate,dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acidand vinylsulfonic acids.
 2. The film of claim 1, wherein saidethylene/vinyl acetate polymer comprises up to 40 wt. % vinyl acetate.3. The film of claim 2, wherein said ethylene/vinyl acetate polymercomprises 14-22 wt. % vinyl acetate.
 4. The film of claim 1, whereinsaid hydrophilic monomer comprises acrylic acid.
 5. The film of claim 4,wherein said ethylene/vinyl acetate polymer comprises 22-33 wt. %acrylic acid.
 6. The film of claim 5, wherein said ethylene/vinylacetate polymer is an ethylene/vinyl acetate graft copolymer comprising14-33 wt. % vinyl acetate and having 22-30 wt. % acrylic acid graftedthereto.
 7. The film of claim 6, wherein said graft copolymer comprises14-22 wt. % vinyl acetate and has 26 wt. % acrylic acid grafted thereto.8. The film of claim 4, wherein said ethylene/vinyl acetate polymer isan ethylene/vinyl acetate graft copolymer containing 30-36 wt. % vinylacetate and having 26 wt. % acrylic acid grafted thereto.
 9. The film ofclaim 1, wherein said hydrophilic inclusions consist of a hydrophilicpolymer formed from a mixture of acrylic acid/N-vinylpyrrolidone oracrylamide/N-vinylpyrrolidone.
 10. The film of claim 1, wherein saidinclusions consist of a hydrophilic polymer formed from acrylamide. 11.The film of claim 1, having a thickness of 50-500 microns.
 12. The filmof claim 1, comprising up to 40 wt. % of said active principle.
 13. Thefilm of claim 12, wherein said active principle is selected from thegroup consisting of non-steroidal anti-inflammatory agents,17β-oestradiol, progestogen, anticholinesterases, trinitrin, nicotine,morphine, dihydroergotamine, physostigmine, bromocriptine and salicylicacid.
 14. The film of claim 13, wherein said active principle is17β-oestradiol.
 15. The film of claim 13, wherein said active principleis a mixture of oestradiol and progestogen.
 16. The film of claim 13,wherein said active principle is physostigmine.
 17. The film of claim13, wherein said active principle is trinitrin.
 18. The film of claim13, wherein said active principle is nicotine.
 19. The film of claim 13,wherein said active principle is dihydroergotamine.
 20. The film ofclaim 13, wherein said active principle is bromocriptine.
 21. The filmof claim 13, wherein said active principle is salicylic acid.
 22. Thefilm of claim 13, wherein said active principle is a non-steroidalanti-inflammatory agent selected from the group consisting of ketoprofenand ibuprofen.
 23. The film of claim 12, further comprising apermeability stimulator selected from the group consisting of alcoholsand polyols.
 24. A transdermal system, comprising:an occlusive support,the active principle-containing film of claim 1 in contact with saidsupport, an adhesive interface in contact with said activeprinciple-containing film, and a protective film in contact with saidadhesive interface.
 25. A transdermal system comprising:an occlusionsupport, an active principle-containing film comprising a hydrophobicethylene/vinyl acetate polymer containing at least one active principleand composed of 10-50 wt. % of hydrophilic inclusions consisting of ahydrophilic polymer formed from at least one hydrophilic monomerselected from the group consisting of acrylamide, ethylene glycolacrylate, methylolacrylamide, diacetone acrylamide, maleic acid, acrylicacid, fumaric acid, itaconic acid, propylene glycol acrylate, ethyleneglycol methacrylate, methacrylamide, methacrylic acid, propylene glycolmethacrylate, hydroxyethyl methacrylate, dimethylaminoethylmethacrylate, N-vinylpyrrolidone, vinylacetic acid and vinyl sulfonicacids, in contact with said support, an adhesive interface in contactwith said active principle-containing film, and a protective film incontact with said adhesive interface.
 26. The transdermal system ofclaim 24 or 25, wherein said occlusive film is selected from the groupconsisting of polyvinylidene dichlorides, polyethylenes,ethylene/polyvinyl alcohols, polypropylenes, polyesters,polychlorotrifluoroethylenes and combinations thereof with a metalsheet, andsaid adhesive interface is chemically inert with respect tosaid active principle-containing film and is selected from the groupconsisting of acrylic polymers, polyurethanes, silicones andethylene/vinyl acetate polymers.
 27. The transdermal system of claim 24or 25, wherein said active principle-containing film is anethylene/vinyl acetate-acrylic acid graft copolymer.
 28. The transdermalsystem of claim 27, wherein said ethylene/vinyl acetate-acrylic acidgraft copolymer comprises 18 wt. % vinyl acetate and 26 wt. % acrylicacid.
 29. The transdermal system of claim 24 or 25, wherein said activeprinciple-containing film is an ethylene/vinyl acetate-acrylamide graftcopolymer.
 30. The transdermal system of claim 24 or 25, wherein saidactive principle-containing film further comprises a permeabilitystimulator selected from the group consisting of alcohols and polyols.31. The transdermal system of claim 24 or 25, wherein said activeprinciple-containing film comprises at least two active principles. 32.The transdermal system of claim 24 or 25, wherein said active principleis distributed throughout said active principle-containing film.
 33. Thetransdermal system of claim 31, wherein said active principle-containingfilm has at least two regions and said at least two active principlesare separately distributed in said at least two regions.
 34. A processfor the preparation of the film of claim 1, comprising the steps of:(a)contacting a hydrophobic ethylene/vinyl acetate polymer with at leastone hydrophilic monomer selected from the group consisting ofacrylamide, methylolacrylamide, diacetone acrylamide, maleic acid,acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate,ethylene glycol methacrylate, methacrylamide, methacrylic acid,propylene glycol methacrylate, hydroxyethyl methacrylate,dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acidand vinylsulfonic acids to form a mixture, (b) irradiating said mixturefor simultaneously polymerizing said hydrophilic monomers to formhydrophilic polymer and grafting said hydrophilic polymer onto saidhydrophobic ethylene/vinyl acetate polymer to form an ethylene/vinylacetate copolymer having grafted thereto said hydrophilic polymer, toobtain an ethylene/vinyl acetate graft copolymer having a degree ofgrafting of said hydrophilic polymer of 10-50% to form a copolymermatrix, (c) charging said ethylene/vinyl acetate polymer or saidcopolymer matrix with an active principle, and (d) shaping saidcopolymer matrix or said charged copolymer matrix to form a film. 35.The process of claim 34, wherein said irradiating and polymerizing step(b) is carried out in a liquid medium in the presence of an inhibitor ofhomopolymerization of said hydrophilic monomer.
 36. The process of claim34, wherein said irradiating and polymerizing step (b) is carried out ina liquid medium in the presence of a copolymerizable crosslinking agent.37. The process of claim 35, wherein said copolymerizable crosslinkingagent is selected from the group consisting of methylenebisacrylamide,divinylbenzene, triallyl cyanurate, ethylene, butylene glycol acrylates,butylene glycol methacrylates, tetraethylene glycol acrylates,tetraethylene glycol methacrylates and triallyl orthophosphate.
 38. Theprocess of claim 34, wherein said irradiating and polymerizing step (b)is carried out by irradiating with ionizing radiation to provide a totalirradiation dose of between 0.5-50 kGy.
 39. The process of claim 34,wherein said charging step (c) is carried out before said shaping step(d).
 40. The process of claim 34, wherein said charging step (c) iscarried out after said shaping step (d).
 41. The process of claim 34,wherein said charging step (c) comprises steeping said active principleinto said ethylene/vinyl acetate polymer or said copolymer matrix,dispersing said active principle into said ethylene/vinyl acetatepolymer or said copolymer matrix, diffusing said active principle intosaid ethylene/vinyl acetate polymer or said copolymer matrix from asupport impregnated with said active principle, or immersing saidethylene/vinyl acetate polymer or said copolymer matrix in a saturatedvapor atmosphere of said active principle.
 42. The process of claim 34,wherein said shaping step (d) is carried out by extrusion.
 43. A processfor the preparation of the film of claim 1, comprising the steps of:(a)irradiating a hydrophobic ethylene/vinyl acetate polymer in the powder,granule, or film form, at a dose between 10-80 kGy, (b) storing theirradiated ethylene/vinyl acetate polymer, (c) contacting said storedirradiated ethylene/vinyl acetate polymer with at least one hydrophilicmonomer selected from the group consisting of acrylamide,methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid,fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycolmethacrylate, methacrylamide, methacrylic acid, propylene glycolmethacrylate, hydroxyethyl methacrylate, dimethylaminoethylmethacrylate, N-vinylpyrrolidone, vinylacetic acid, and vinylsulfonicacids to form an ethylene/vinyl acetate copolymer having grafted theretosaid hydrophilic monomer in the form of a hydrophilic polymer, to obtainan ethylene/vinyl acetate graft copolymer having a degree of grafting ofsaid hydrophilic polymer of 10-50%, to form a copolymer matrix, (c)charging said ethylene/vinyl acetate polymer or said copolymer matrixwith an active principle, and (d) shaping said copolymer matrix or saidcharged copolymer matrix to form a film.
 44. A process for thepreparation of an ethylene/vinyl acetate graft copolymer having graftedthereto hydrophilic monomers in the form of a hydrophilic polymer,comprising the steps of:(a) irradiating a hydrophobic ethylene/vinylacetate polymer in the powder, granule, or film form, at a dose between10-80 kGy, (b) storing the irradiated ethylene/vinyl acetate polymer,(c) contacting said stored irradiated ethylene/vinyl acetate polymerwith at least one hydrophilic monomer selected from the group consistingof acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid,acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate,ethylene glycol methacrylate, methacrylamide, methacrylic acid,propylene glycol methacrylate, hydroxyethyl methacrylate,dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid,and vinylsulfonic acids to form an ethylene/vinyl acetate copolymerhaving grafted thereto said hydrophilic monomer in the form of ahydrophilic polymer, to obtain an ethylene/vinyl acetate graft copolymerhaving a degree of grafting of said hydrophilic polymer of 10-50%, toform a copolymer matrix.